Zurich Open Repository and Archive. Long-term survival of glioblastoma patients treated with radiotherapy and lomustine plus temozolomide

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1 University of Zurich Zurich Open Repository and Archive Winterthurerstr. 190 CH-8057 Zurich Year: 2009 Long-term survival of glioblastoma patients treated with radiotherapy and lomustine plus temozolomide Glas, M; Happold, C; Rieger, J; Wiewrodt, D; Bähr, O; Steinbach, J P; Wick, W; Kortmann, R; Reifenberger, G; Weller, M; Herrlinger, U Glas, M; Happold, C; Rieger, J; Wiewrodt, D; Bähr, O; Steinbach, J P; Wick, W; Kortmann, R; Reifenberger, G; Weller, M; Herrlinger, U (2009). Long-term survival of glioblastoma patients treated with radiotherapy and lomustine plus temozolomide. Journal of Clinical Oncology, 27(8): Postprint available at: Posted at the Zurich Open Repository and Archive, University of Zurich. Originally published at: Journal of Clinical Oncology 2009, 27(8):

2 JCO/2008/ Glas et al. 1 Long-term survival of glioblastoma patients treated with radiotherapy and lomustine plus temozolomide Martin Glas 1*, Caroline Happold 2,3*, Johannes Rieger 2,4, Dorothee Wiewrodt 5, Oliver Bähr 2,4, Joachim P. Steinbach 2,4, Wolfgang Wick 2,6, Rolf-Dieter Kortmann 7, Guido Reifenberger 8, Michael Weller 2,3, Ulrich Herrlinger 1,2 1 Division of Clinical Neurooncology, Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, D Bonn, Germany, Tel.: , Fax: Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, D Tübingen, Germany, Tel.: , Fax: Department of Neurology, University Hospital Zürich, Frauenklinikstrasse 26, CH-8091 Zürich, Switzerland, Tel.: , Fax: Dr. Senckenbergisches Institut of Neurooncology, University of Frankfurt, Schleusenweg 2-16, D Frankfurt am Main, Germany, Tel.: , Fax: Department of Neurosurgery, University of Mainz, Langenbeckstr. 1, D Mainz, Germany, Tel , Fax: Department of Neurooncology, University of Heidelberg, Germany, Im Neuenheimer Feld 400, Heidelberg, Germany, Tel.: , Fax: Department of Radiation Oncology, University of Leipzig, Stephanstrasse 9a, D Leipzig, Germany, Tel.: , Fax: Department of Neuropathology, Heinrich-Heine-University of Duesseldorf, Moorenstr. 5, D Düsseldorf, Germany, Tel , Fax * Authors contributed equally to this work. Running head: Long-term survival after lomustine plus temozolomide therapy of glioblastoma This manuscript contains only original material and has not been published elsewhere. Address for correspondence: Ulrich Herrlinger, MD, Division of Clinical Neurooncology, Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, D Bonn, Germany, Tel.: , Fax: , Ulrich.Herrlinger@ukb.uni-bonn.de Abstract

3 JCO/2008/ Glas et al. 2 Purpose: To evaluate long-term survival in a prospective series of newly diagnosed glioblastoma patients treated with a combination of lomustine (CCNU), temozolomide (TMZ) and radiotherapy. Patients and methods: Thirty-nine patients received radiotherapy of tumor site only (60 Gy) and CCNU/TMZ chemotherapy (n=31 with standard dose CCNU 100 mg/m 2 (day 1), TMZ 100 mg/m 2 /d (day 2 to 6); n=8 with intensified dose CCNU 110 mg/m 2 (day 1), TMZ 150 mg/m 2 (day 2 to 6)) for up to 6 courses. Results: In the whole cohort, the median overall survival (mos) was 23.1 months with 47.4% surviving for 2 years and 18.5% for 4 years. After a median follow-up of 41.5 months, mos has not been reached in the intensified group and is significantly higher than in the standard group (22.6 months; p=0.024). In the intensified group, 4 of 8 patients survive for at least 56 months, two of them without recurrence. O6- methylguanine-dna methyltransferase (MGMT) gene promotor methylation in the tumor tissue was associated with a significantly longer mos (methylated 34.3 months vs. non-methylated 12.5 months). A multivariate Cox proportional hazard model revealed MGMT status (methylated vs. non-methylated, relative risk (RR) of death 0.43, p=0.003) and chemotherapy dose (intensified vs. standard, RR 0.37, p=0.012) as independent prognostic factors. WHO grade 4 hematoxicity was observed more frequently in the intensified group (57% vs. 16%). Conclusion: The combination of radiotherapy, CCNU and TMZ yielded promising long-term survival data in newly diagnosed glioblastoma. Intensification of CCNU/TMZ chemotherapy may add an additional survival benefit albeit with higher acute toxicity.

4 JCO/2008/ Glas et al. 3 Introduction Despite recent improvements in surgery and combined radiochemotherapy, glioblastoma remains a devastating disease. Standard radiochemotherapy includes concomitant and adjuvant temozolomide (TMZ) chemotherapy and leads to a median progression-free survival (mpfs) of 6.9 months and a median overall survival time (mos) of 14.6 months. 1 Using a combination of TMZ and lomustine (CCNU) in the UKT-03 trial, we have previously reported promising survival data with a mpfs of 9 months and a high mos of 22.6 months. 2 Thirteen of 31 patients in the UKT-03 trial were alive at the end of the 24 months follow-up period reported in the previous publication. 2 In our present analysis carried out 55 months after the accrual of the last patient to the trial, we report mature data on long-term survival in the UKT-03 cohort. Furthermore, we added the previously unpublished data set of a pilot group of 8 patients treated with an intensified CCNU/TMZ regimen that might confer even higher rates of long-term survival. Overall, we report on the long-term survival of 39 prospectively documented patients receiving radiotherapy and combined CCNU/TMZ chemotherapy as first-line therapy for glioblastoma.

5 JCO/2008/ Glas et al. 4 Patients and methods This prospective series of patients treated with CCNU and TMZ includes 31 patients treated in the UKT-03 trial 2 and 8 patients treated in a prospective pilot group with increased CCNU and TMZ doses. All patients received treatment at the University of Tuebingen (Dept. of Neurology, Tuebingen, Germany) and Mainz (Dept. of Neurology and Neurosurgery, Mainz, Germany) Medical Centers. The main inclusion criteria for both groups were histological diagnosis of glioblastoma, surgery no longer than 21 days before, no prior radiotherapy or chemotherapy, age older than 18 years, Karnofsky performance score (KPS) of 70% or higher, and no alterations in bone marrow reserve, liver function, or renal function. Both treatment regimens were approved by the local Ethics Committees. All patients gave written informed consent. In all patients, the therapy-independent prognostic factors KPS at entry into the study and the extent of resection as determined by the neurosurgeon were defined. Furthermore, the study population was assigned to one of the prognostic groups developed by recursive partitioning analysis 3 and validated in a large number of glioma patients enrolled in Radiation Therap Oncology Group trials. 4 The chemotherapy schedule included oral CCNU 100 mg/m 2 on day 1 followed by TMZ 100 mg/m 2 /d on days 2-6 of 6-week courses ( standard group ). The patients of the pilot cohort received a dose intensification with CCNU 110 mg/m 2 on day 1 followed by TMZ 150 mg/m 2 /d on days 2-6 ( intensified group ). A maximum of 6 courses were delivered with individual dose adjustments in subsequent courses and discontinuation rules as previously described. 2 Radiotherapy was delivered during courses 1 and 2 as involved-field radiotherapy with a total dose of 60 Gy in single daily fractions of 2 Gy. Toxicity of the CCNU/TMZ treatment regimen was continously monitored throughout the treatment and follow-up phase in the whole cohort. O 6 -

6 JCO/2008/ Glas et al. 5 methylguanine methyltransferase (MGMT) promoter methylation status was analyzed in all available samples by methylation-specific PCR as previously described. 2, 5 Response assessment was based on contrast-enhanced MRI after courses 2, 4, and 6. 6 After chemotherapy, patients were followed at 3 months intervals by clinical examination and contrast-enhanced MRI. All patients were assessed for progressionfree survival upon CCNU/TMZ and subsequent therapies, overall survival and late toxicity. PFS and OS were calculated from the day of surgery leading to the histologic diagnosis of GBM. Second PFS were calculated from the day of diagnosis of recurrence on MRI. Survival data were analyzed according to the Kaplan-Meier method using the logrank test for comparisons between different groups. Also, the influence of the MGMT promoter methylation status (methylated vs. non-methylated), CCNU/TMZ dosing (intensified vs. standard), extent of resection (complete vs. incomplete resection or biopsy) and RTOG RPA class (class III vs. class IV or V) was analyzed in univariate regression analyses using a Cox proportional hazards model. Parameters with a significant influence on survival in the univariate analysis were also analyzed in a multivariate analysis.

7 JCO/2008/ Glas et al. 6 Results Patient characteristics and therapy applied Thirty-nine patients were accrued between March 2002 and December Thirtyone patients were treated in the UKT-03 trial ( standard group ) and 8 patients were treated with higher doses of CCNU and TMZ in an additional pilot group ( intensified group ). Patients characteristics are summarized in Table 1. The patients of the intensified group were older than the UKT-03 patients (median age 59 vs. 51 years) but did not differ with respect to KPS. The patients in the intensified group received a median of 3.5 courses CCNU/TMZ (range, 1-6 courses), patients of the UKT-03 group received a median of 4.5 courses (range, 1-6 courses). Twenty-seven patients (69%) received second-line therapy with a mpfs of 6 months. Eleven of 27 patients had an additional tumor resection at recurrence. Reirradiation was applied in 7 patients (mpfs 4 months) and hyperthermia in one patient. Second-line chemotherapy consisted of intensified TMZ in 10 patients (mpfs 7,5 months) and ACNU/VM26 in 8 patients (mpfs 3 months). Third-line (n=11, mpfs 4 months) and fourth-line therapy (n=3, mpfs 2 months) included reirradiation, intensified TMZ, ACNU, CCNU, pegylated liposomal doxorubicine and imatinib/hydroxyurea. Toxicity Acute toxicity was higher in the intensified cohort than in the standard group with grade 4 myelotoxicity occuring in 4 of 7 evaluable patients (57%) compared to 16% in the cohort of 31 patients treated with standard-dose CCNU/TMZ. As with the standard dose 2, one patient died from septicemia during myelosuppression. No nonhematological acute or delayed toxicity was observed.

8 JCO/2008/ Glas et al. 7 There were no signs of therapy-dependent late neurotoxicity in the long-term surviving patients. In all 3 patients who have survived without recurrent disease, the KPS months after inclusion into the trial has not decreased. Two of three patients who had one recurrence had a decrease of KPS, from 100% to 70% and from 80% to 50%, upon progression, but have remained on a stable KPS upon successful treatment of recurrence. One additional patient has remained on a stable KPS of 100% despite recurrence. In summary, decreases in KPS in some long-term survivors were attributable to recurrent disease, but not to CCNU/TMZ therapy. Long-term survival and dependency on MGMT promoter methylation status In the whole cohort of 39 patients, the mpfs was 10 months (range months). The mos was 23.1 months (Fig. 1). Overall survival was 47.4% at 2 years, 26.4% at 3 years, 18.5% at 4 years, and 15.8% at 5 years. Four of 39 patients (10.3%) have had no recurrence so far. Two of 8 patients in the intensified group (25%) have remained recurrence-free. Eight of 19 investigated patients in the standard group and 3 of 4 investigated patients of the intensified group had a methylated MGMT promotor. Survival strongly depended on the MGMT promoter methylation status. Median PFS (Fig. 2a) was significantly higher in the methylated group (19 months, n=11) than in the nonmethylated group (7 months, n=12) (p=0.0064). This also translated into a substantial overall survival benefit (Fig. 2b) for patients with a methylated MGMT promoter: median OS was 12.5 months for non-methylated patients, but 34.3 months for

9 JCO/2008/ Glas et al. 8 methylated patients (p=0.0009). In the methylated group, 45% of patients survived 3 years and 36% of patients survived 5 years. Influence of dose escalation on survival In the standard group, the mpfs was 9 months (range, 1.9 to 54+ months; Fig. 3a) and the mos was 22.6 months. 2 The long-term survival analysis now shows 41.9% of patients surviving 2 years, 16.9% of patients surviving 3 years and 9.7% surviving 4 years (Fig. 3b). In contrast, the 8 patients in the intensified group had a mpfs of 26 months and mos was not yet reached after a median follow-up time of 41.5 months (range, month). Both PFS (p=0.014) and OS (p=0.024) were significantly higher in the intensified group than in the standard group. Four of 8 patients in the intensified group are currently surviving for at least 56 months, 2 of them without any recurrence or signs of late neurotoxicity. Of the 4 patients in the intensified group which could be assessed for MGMT promoter status, the 3 patients with a methylated promoter are all still surviving after a follow-up time of months while the patient with a non-methylated MGMT promoter has died after 28 months. A univariate Cox proportional hazards analysis identified MGMT promoter methylation status and chemotherapy dose as factors which have an influence on survival (Table 2). In contrast, extent of resection and RTOG RPA class have no such effect. A subsequent multivariate analysis confirmed that the presence of a methylated MGMT promoter and the application of intensified CCNU/TMZ were associated with a significantly reduced risk of death (Table 2).

10 JCO/2008/ Glas et al. 9 Discussion The data presented here suggest that the combination of CCNU, TMZ, and radiotherapy has very encouraging activity in patients with newly diagnosed glioblastoma and may lead to a substantial rate of patients with long-term survival. The rate of long-term survivors >24 months is stunning with almost 50% in the whole cohort. This might be the best rate ever observed in a prospective glioblastoma analysis and does not appear to be bias-driven. 2 The fact that patients with a nonmethylated MGMT promoter in our trial survived only 12.5 months which is virtually identical to the median survival seen in previous trials 7 suggests that the patients in our series have not been selected for good therapy-independent prognostic factors. The increased 2-year survival rate is biologically meaningful in that patients who benefit from chemotherapy seem to have a potential for long-term survival. Although historical comparisons may not be legitimate, CCNU/TMZ almost doubled the percentage of survivors at 24 months (47,5%) compared with the EORTC/NCIC trial using TMZ monotherapy (26.5%). 1 The comparison with such historical data has to be taken with caution since MGMT promoter methylation status is not known in many of our patients (41%) and potential differences in the number of patients with methylated MGMT promoter may have a significant impact on survival data. With 16% survivors after 5 years, the rate of patients who are surviving very long and are potentially cured is also increased as compared to the rate of 4-5% that is commonly reported for glioblastoma. 8 In contrast to other studies on long-term survivors with median ages of 40.2 years 8 or 51 years 9, the long-term survivors in our study are not particularly young: the median age was 57 years (range years). Long-term survival is mainly induced by the efficient primary treatment consisting of CCNU/TMZ. Four of 7 patients surviving longer than 4 years have not relapsed so far

11 JCO/2008/ Glas et al. 10 and mpfs was longer during CCNU/TMZ therapy (mpfs 10 months) than during second-line therapy (mpfs 6 months) or further salvage therapies. However, the high rate of patients receiving a second resection (28%) or multiple salvage therapies or both might influence the overall survival to some extent. As in the UKT-03 cohort, the MGMT promoter status remains a very strong factor to predict the benefit from therapy in the whole cohort of patients treated with standard or intensified CCNU/TMZ. The median survival time of patients with a nonmethylated MGMT promoter is 12.5 months, essentially the time which is also achieved with radiotherapy alone as the first-line treatment. 1 In patients with a methylated MGMT promoter, the mos (34.5 months) is almost tripled compared to patients with a non-methylated MGMT promoter. Obviously, there is no evidence that a CCNU/TMZ-induced MGMT depletion breaks resistance to chemotherapy in MGMT-non-methylated patients. Thus, patients with a non-methylated MGMT promoter in their tumor may not take benefit from CCNU/TMZ at any dose. Consequently, future trials with combined CCNU/TMZ chemotherapy or other alkylating combination chemotherapy may be restricted to patients with a methylated MGMT promoter or should be at least stratified according to MGMT promoter methylation status. A significant dose intensification of TMZ in the CCNU/TMZ combination therapy appears to add an additonal marked survival benefit in the presence of high but tolerable toxicity. Admittedly, the group of patients with intensified CCNU/TMZ is small and conclusions are therefore limited, particularly because the MGMT promoter methylation status is not known in many of the patients. Nevertheless, PFS and OS in this group are substantially increased and the mos in the mixed group of MGMT-

12 JCO/2008/ Glas et al. 11 methylated and non-methylated patients treated with intensified CCNU/TMZ appears to be higher than the mos of the standard dose patients with a methylated MGMT promotor (41.5+ vs months). Most intriguingly, 4 of 8 patients in the intensified group are currently surviving for at least 56 months, 2 of them without recurrence. It is important to note that the excellent efficacy data in the intensified group may not be due to a selection of patients with favourable prognostic factors. The inclusion criteria were identical to the inclusion criteria of a previous large phase III trial. 1 More importantly, the median age (59.5 years) as a major prognostic factor was higher than in previous trials and close to the average age of patients with newly diagnosed glioblastoma in the general population. In conclusion, the combination of CCNU and TMZ shows very promising efficacy against newly diagnosed glioblastoma. The data presented here demonstrate an encouraging therapeutic potential but also the toxic limitations of the dose-intensified regimen in this setting. Further studies are warranted to optimize CCNU/TMZ combination chemotherapy.

13 JCO/2008/ Glas et al. 12 Table 1: Demographic data of 39 patients treated with CCNU and temozolomide Characteristic Patients (n) Patients (%) Age < 50 years 50 years Sex Male Female KPS Extent of surgery Complete resection Partial resection Biopsy NA RTOG RPA class Class III Class IV Class V Abbreviations: KPS, Karnofsky performance score; RTOG RPA, Radiation Therapy Oncology Group recursive partitioning analysis; NA, not assessable.

14 JCO/2008/ Glas et al. 13 Table 2: Univariate and multivariate Cox regression analysis for factors potentially influencing overall survival in 39 patients treated with CCNU and temozolomide Univariate analysis Median survival in months (No. of patients) Hazard ratio (lower-upper 95% CI) Condition 1 Condition 2 Condition 1 vs. 2 p* RTOG RPA class Extent of resection MGMT promoter status CCNU/TMZ dosing Multivariate analysis III 22.9 (8) Complete 27.5 (14) Methylated 34.3 (11) Intensified >41.5 (8) IV or V 24.8 (31) 1.06 ( ) 0.78 Partial or biopsy 22.6 (23) 0.89 ( ) 0.52 Nonmethylated 12.5 (12) 0.40 ( ) Standard 22.6 (31) 0.52 ( ) MGMT promoter status Methylated 34.3 Nonmethylated ( ) CCNU/TMZ dosing Intensified >41.5 (8) Standard 22.6 (31) 0.37 ( ) Abbreviations: CI, confidence interval; CCNU, lomustine; TMZ, temozolomide; MGMT, O6- methylguanine-dna methyltransferase; RTOG RPA, Radiation Therapy Oncology Group recursive partitioning analysis which integrates data on performance score, age and extent of resection; *chi-square test.

15 JCO/2008/ Glas et al. 14 Supplement 1: Salvage therapy applied to 27 patients receiving CCNU/TMZ as firstline therapy Patient OS Second-line therapy Third-line therapy Fourth-line t herapy No. Treatment PFS [m] Treatment PFS [m] Treatment PFS [m] Resection + TMZ 7/ TMZ 7/ ACNU / VM Resection + TMZ 7/7 5 Resection + TMZ 7/7 4 CCNU Resection + ACNU / VM26 1, ACNU / VM RT 2 RT + TMZ 7/7 5 Resection + ACNU Resection + TMZ 7/7 9 RT + imatinib / HU TMZ 7/ Resection+ ACNU / VM26 19 RT + imatinib / HU Resection + TMZ 7/7 6 RT Resection+ ACNU / VM RT 6 ACNU Resection + TMZ 7/7 6 imatinib / HU Hyperthermia 9 imatinib / HU 4 TMZ 7/ Resection + TMZ 7/7 7 RT ACNU / VM RT Resection + RT ACNU / VM26 8 Peg-DOX ACNU / VM RT TMZ 7/ Resection RT 6 TMZ 7/ RT TMZ 7/ Abbreviations: CCNU, lomustine; imatinib / HU, imatinib / hydroxyurea; ACNU / VM26, nimustine / teniposide; OS, overall survival in months after primary diagnosis; PFS, progression-free survival in months; Resection, tumor resection; RT, radiotherapy; TMZ 7/7, intensified temozolomide, alternating weekly regimen; Peg-Dox, pegylated liposomal doxorubicine. +censored observation.

16 JCO/2008/ Glas et al. 15 Figure legends Figure 1: Overall survival (OS) in the cohort of 39 patients receiving CCNU/TMZ combined with radiotherapy as first-line therapy for glioblastoma. Figure 2: (a) PFS and (b) OS according to the MGMT promoter methylation status in 23 evaluable patients (12 unmethylated, 11 methylated). Differences in survival between the two groups were statistically significant (logrank test; p= for PFS and p= for OS). Figure 3: (a) PFS and (b) OS according to the chemotherapy dosing. Thirty-one patients received standard dose chemotherapy (standard, CCNU 100 mg/m 2 on day 1, TMZ 100 mg/m 2 on day 2-6) and 8 patients received intensified dose chemotherapy (intensified, CCNU 110 mg/m 2 on day 1, temozolomide 150 mg/m 2 on day 2-6). Differences in survival between the two groups were statistically significant (logrank test; p=0.014 for PFS and p=0.024 for OS).

17 JCO/2008/ Glas et al. 16 References 1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: , Herrlinger U, Rieger J, Koch D, et al. Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J Clin Oncol 24: , Curran WJ, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85: , Scott CB, Scarantino C, Urtasun R, et al. Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: A report using RTOG Int J Radiat Oncol Biol Phys 40:51-55, Möllemann M, Wolter M, Felsberg J, et al. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer 113: , Macdonald DR, Cascino TL, Schold SC Jr, et al. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8: , Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352: , McLendon RE, Halperin EC. Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer 98: , Krex D, Klink B, Hartmann C, et al. Long-term survival with glioblastoma multiforme. Brain 130: , 2007

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